Download Role of Antigen-Presenting Cells in Innate Immune System

Archivum Immunologiae et Therapiae Experimentalis, 2001, 49, Suppl. 1, S47–S52
PL ISSN 0004-069X
Review
Role of Antigen-Presenting Cells in Innate Immune System
T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
TOSHIAKI OHTEKI* and SHIGEO KOYASU
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
Japan
Abstract. Activation of antigen-presenting cells (APC) and natural killer (NK) cells initiates the production of
various proinflammatory cytokines including interleukin 12 (IL-12), interferon γ (IFN-γ) and nitric oxide (NO),
which are important in the innate immune response for controlling infection by intracellular pathogens. In this
review, we focus on these cytokines produced by APC and summarize the current understanding of how APC
functions are regulated by cytokines in innate immunity.
Key words: dendritic cells; macrophages; IL-12; IL-15; IFN-γ; NO; γc; IL-2/15Rβ.
Introduction
The innate immune system is thought to have predated the adaptive immune response. Indeed, innate
host defense mechanisms are found in all multicellular
organisms, whereas adaptive immunity is found only in
vertebrates. Interleukin 12 (IL-12), which is produced
by antigen-presenting cells (APC) upon infection by
micro-organisms, is a critical cytokine for triggering innate immune responses. Likewise, IL-12 production is
a prerequisite for the activation of T helper type 1
(Th1) cell-mediated type 1 immune responses in adaptive immunity (Fig. 1)29, 39, 60. One of the most distinctive and important activities of IL-12 is its ability to
induce interferon γ (IFN-γ) production by multiple cell
types including natural killer (NK) cells and APC in
innate immunity, and Th1 cells in adaptive immunity.
In contrast to IL-12 and IFN-γ, IL-10 and several other
Abbreviations used: DC – dendritic cells, IL – interleukin, NO – nitric oxide, γc – cytokine common gamma subunit, Th1 – T helper
type 1, APC – antigen-presenting cells, iNOS – inducible nitric oxide synthase, IRF – interferon regulatory factor.
* Correspondence to: Toshiaki Ohteki, Ph.D., Department of Microbiology and Immunology, Keio University School of Medicine,
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, tel.: +81 3 3353 1211 ext. 62696, fax: +81 3 5361 7658, e-mail: tohteki@
microb.med.keio.ac.jp
cytokines antagonize these pathways by blocking IL-12
production7, 24. In fact, studies using neutralizing antibodies against IFN-γ and mice deficient for IL-12, IFN-γ,
or IL-10 have documented the essential roles of these
cytokines in controlling the resistance against intracellular pathogens including bacteria, fungi and protozoa7,
10, 13, 24, 28, 37, 63
. IFN-γ produced by the effect of IL-12,
in turn, acts on macrophages to express inducible NO
synthase (iNOS) essential for nitric oxide (NO) production (Fig. 1). NO is one of the important effector molecules to eradicate infecting microbes. For example,
in the absence of iNOS activity, IL-12 was unable
to prevent the spread of Leishmania parasites15, 16.
IFN-γ is thus an important cytokine, playing a major
role in activating macrophages to kill infecting micro-organisms.
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T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
APC as Major IFN-γ Producers in Innate
Immune Responses
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NK cells have been considered to be major producers of IFN-γ in an early stage of infection. Studies with
various microbes, including Listeria monocytogenes,
Toxoplasma gondii and Leishmania major, revealed
that IL-12 derived from dendritic cells (DC) and activated macrophages stimulates NK cells to produce
IFN-γ29, 39, 60. Several studies indicated, however, that
IFN-γ is also produced by APC, including macrophages
and DC. Murine14, 23, 40, 45, 56 or human19 macrophages
produce IFN-γ in response to various stimuli such as
LPS23, IFN-γ14, L. monocytogenes56, IL-1245, IL-12 plus
IL-1840, and Mycobacterium tuberculosis19. Since IFN-γ
is one of the most potent up-regulators of IL-12, MHC
class II, CD40 and iNOS expression in macrophages, it
is possible that IFN-γ produced by macrophages is involved as a critical cytokine in an autocrine activation
pathway (Fig. 2)40. In addition, IFN-γ prevents apoptotic death of macrophages by inducing p21waf1 and arresting their cell cycles65.
The other type of APC capable of producing IFN-γ
is DC. DC are the most efficient APC to activate naive
T cells. Endocytosis and the processing of antigens by
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immature DC allow them to mature with the ability to
migrate into T cell area of secondary lymphoid organs6, 12.
Upon maturation, they lose their ability to capture and
process antigens, but, instead, they express high levels
of MHC class II molecules loaded with antigenic peptides and costimulatory molecules, such as CD40,
CD80, and CD86. Consequently, naive T cells are activated by recognizing peptide/MHC complexes and express CD154 at a high level. Activated T cells, in turn,
activate DC through CD40-CD154 interaction48. CD40-CD154 interaction is also important in the survival of
DC in T cell areas. In mice, there are at least two different
types of DC57, 61, 62, 64. They differ in surface phenotype,
origin (myeloid versus lymphoid), the cytokine required
for their development (GM-CSF versus IL-3), and biological function. Recent studies indicated that CD8α+ lymphoid DC (LDC) are able to induce a Th1 response,
whereas CD8α– myeloid DC (MDC) induce a Th2 response38, 46, 55. In addition, it has been reported that DC
derived from Peyer’s patches (PP)30 and the liver33, but
not from the spleen, were found to prime naive T cells
for the production of IL-4 and IL-10, both of which are
Th2 cytokines. These results suggest that DC of different
origin and those residing in different tissues are capable
of inducing distinct immune responses.
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APC
Microbes
NO
IFN-γ
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IL-10
IL-12
IL-18
TNF-α
IL-1
IL-12
IL-18
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Innate immunity
Fig. 1. Innate immunity and Th1 differentiation. Activation of macrophages and DC by infectious agents leads to secretion of IL-12, which
subsequently induces IFN-γ production by NK cells and directs Th1 development. IFN-γ, in turn, acts on monocytes to augment IL-12
secretion and to produce NO, which eradicates infecting microbes. Thus, IL-12 and IFN-γ comprise a positive feedback system
.
Acquired immunity
.
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T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
and mouse, DC can be generated from CD34+ bone-marrow precursors11, 51 and CD14+ monocytes with
GM-CSF in combination with TNF-α or IL-466. These
cells, however, secrete little amount of IFN-γ47 (our
unpublished data). It is possible that only a subpopulation of DC produce IFN-γ, depending on their origin
and the location where the DC reside, as discussed
above. Alternatively, it is possible that employment of
cytokines during the differentiation of DC artificially
down-regulates the ability of DC precursors to produce
IFN-γ. Human DC freshly prepared without any cytokine supplement should be tested for their ability to
produce various cytokines, including IFN-γ.
4
We and others have recently demonstrated that mature DC express IL-12 receptors27, 44 and are capable of
producing significant amounts of IFN-γ in an IL-12-dependent manner44. The amounts of IFN-γ from DC and
macrophages are much higher than those from NK
cells44. Although IL-12 and IFN-γ are produced by both
LDC and MDC, LDC are the major producers of IL-12
and IFN-γ38, 44. IL-2, IL-4 and IL-18 augment IL-12-dependent IFN-γ production by mature DC21, 22. It
should be noted that DC are able to produce IL-12 and
IFN-γ during antigen presentation as a result of CD40-CD154 interaction21, implying the importance of DC-derived IL-12 and IFN-γ in Th1 development during
antigen presentation. Since IL-12 is produced by DC
independently of T cells52, DC-derived IL-12 triggers
an autocrine activation pathway between IL-12 and
IFN-γ as described in macrophages22, 27, 44 (Fig. 2).
Like murine DC, human DC are classified into at
least two subpopulations, namely DC1 (myeloid DC)
and DC2 (lymphoid DC). Contrary to murine DC, it
appears that DC1 and DC2 induce Th1 and Th2 responses, respectively49. Upon CD40 ligation, DC1 produce
IL-1, IL-6, IL-8, IL-10 and IL-12, whereas DC2 secrete
IL-8 but not other cytokines tested49. Precursors of DC2
produce high levels of IFN-α/β upon viral infection,
suggesting that this population plays a critical role in
the acute phase of viral infection54. In both the human
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The Role of a Cytokine(s) Utilizing a γc-Mediated
Signaling System in APC Functions
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The previous conclusion that NK cells are the major
IFN-γ producers was drawn from the observation that
γc–/–(Y) Rag-2–/– mice lacking all lymphoid cells including NK cells, produce minimal amounts of IFN-γ3. Although DC and macrophages are normally present in
γc–/–(Y) Rag-2–/– mice4, 50, their IFN-γ production in response to IL-12 is impaired44, suggesting the importance of γc-mediated signaling in the functional maturation of DC and macrophages.
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Macrophage
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T cell, NK cell
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Fig. 2. Autocrine APC activation pathway. DC produce IL-12 and IFN-γ in an autocrine manner when triggered by microbial infection.
Once IL-12 and IFN-γ are produced by DC, a positive feedback pathway(s) is activated between DC and macrophages, even in the absence
of NK cell-derived IFN-γ. Macrophages then secrete IFN-γ in response to IL-12, which also activates macrophages in an autocrine manner
to produce NO. IL-2 and IL-4 augument such IL-12-dependent IFN-γ production by APC
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T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
There are at least five cytokines utilizing γc as a subunit of their receptor components. These are IL-2, IL-4,
IL-7, IL-9 and IL-15. Among them, IL-2 and IL-15
share another subunit in their receptor systems, namely
the IL-2/15Rβ subunit. IL-2/15Rβ–/–Rag-2–/– mice also
showed phenotypes similar to those of γc–/–(Y) Rag-2–/–
mice (unpublished data), suggesting that either IL-2 or
IL-15 is critical in the functional maturation of APC.
Recently, two groups independently generated mice
deficient in IL-15Rα34 and IL-1532, and demonstrated
the critical role of the IL-15/IL-15R system in the development of NK cells. Interestingly, IL-15 type-1 receptors, consisting of IL-15Rα, IL-2/15Rβ and γc, are
expressed not only on NK and T cells, but also on APC,
such as DC and macrophages2, 8, 17, 21, 26, 31, implying
the physiological importance of the IL-15/IL-15R system in APC functions. Indeed, IL-15 is required for
LPS-induced TNF-α production by macrophages1.
These studies collectively indicate that IL-15/IL-15R
interaction is critical in the early activation of APC.
Other studies, using neutralizing antibodies against IL-1518 and transgenic mice expressing a dominant-negative form of IL-1542 also suggested that the effect of
IL-15 on IFN-γ induction overlaps with that of IL-12.
As impaired IL-12 production has also been observed
in mice deficient for interferon regulatory factor (IRF)-135, 59, nuclear factor κB (NFκB)41, IFN consensus sequence-binding protein (ICSBP)9, 25, 53, Mkk336, or Eta-15, one of these molecules may function downstream
of the IL-15 receptor.
In humans, patients with X-linked severe combined
immunodeficiency disease (XSCID) have mutations in
the γc gene43, 58. XSCID is characterized by severe impairment of cell-mediated type-1 immune responses.
Our findings of APC defects in mice the lacking γc
gene, an animal model of human XSCID, indicate that
the impairment of APC functions is another possible
factor which may deal a fatal blow to γc–/–(Y) mice and,
likewise, to patients with XSCID upon infection by
micro-organisms.
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2), and IL-15 is a potential cytokine governing such
innate immune responses by regulating the early activation of APC and NK cell development.
Acknowledgment. This work was supported by Grant-in-Aid for
Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan (11140271 to S. Koyasu
and 11770173 to T. Ohteki), a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a Private University,
a Keio University Special Grant-in-Aid for Innovative Collaborative Research Project and a grant from the Japanese Society for the
Promotion of Science (JSPS-RFTF-97L00701) to S. Koyasu.
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T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
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T. Ohteki and S. Koyasu: APC Functions in Innate Immunity
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K
Received in July 2000
Accepted in September 2000